Microprecipitation of nanoparticulate pharmaceutical agents

ABSTRACT

This invention describes the preparation of nanoparticulate pharmaceutical agent dispersion via a process that comprises the dissolution of the said pharmaceutical agent in an alkaline solution and then neutralizing the said solution with an acid in the presence of a suitable surface-modifying, surface-active agent to form a fine particle dispersion of the said pharmaceutical agent. This can be preferably followed by steps of diafiltration clean-up of the dispersion and then concentration of it to a desired level. This process of dispersion preparation leads to microcrystalline particles of Z-average diameters smaller than 400 nm as measured by photon correlation spectroscopy. Various modification of precipitation schemes are described, many of which are suitable for large-scale manufacture of these agent dispersions.

FIELD OF THE INVENTION

This invention deals with microprecipitation of pharmaceautical agents(diagnostic and therapeutic) as stable, colloidal, nanoparticulatedispersions for pharmaceutical use.

BACKGROUND OF THE INVENTION

Bioavailability is the degree to which a drug becomes available to thetarget tissue after administration. Many factors can affectbioavailability including the dosage form and various properties, e.g.,dissolution rate of the drug. Poor bioavailability is a significantproblem encountered in the development of pharmaceutical compositions,particularly those containing an active ingredient that is poorlysoluble in water. Poorly water soluble drugs, i.e., those having asolubility less than about 10 mg/mL, tend to be eliminated from thegastrointestinal tract before being absorbed into the circulation.Moreover, poorly water soluble drugs tend to be unsafe for intravenousadministration techniques, which are used primarily in conjunction withfully soluble drug substances.

It is known that the rate of dissolution of a particulate drug canincrease with increasing surface area, i.e., decreasing particle size.Consequently, methods of making finely divided drugs have been studiedand efforts have been made to control the size and size range of drugparticles in pharmaceutical compositions. For example, dry millingtechniques have been used to reduce particle size and hence influencedrug absorption. However, in conventional dry milling, as discussed byLachman, et al., The Theory and Practice of Industrial Pharmacy, Chapter2, "Milling," p. 45, (1986), the limit of fineness is reached in theregion of 100 microns (100,000 nm) when material cakes on the millingchamber. Lachman, et al. note that wet grinding is beneficial in furtherreducing particle size, but that flocculation restricts the lowerparticle size limit to approximately 10 microns (10,000 nm). However,there tends to be a bias in the pharmaceutical art against wet millingdue to concerns associated with contamination. Commercial airjet millingtechniques have provided particles ranging in average particle size fromas low as about 1 to 50 μm (1,000-50,000 um).

Other techniques for preparing pharmaceutical compositions includeloading drugs into liposomes or polymers, e.g., during emulsionpolymerization. However, such techniques have problems and limitations.For example, a lipid soluble drug is often required in preparingsuitable liposomes. Further, unacceptable large amounts of the liposomeor polymer are often required to prepare unit drug doses. Further still,techniques for preparing such pharmaceutical compositions ten to becomplex. A principal technical difficulty encountered with emulsionpolymerization is the removal of contaminants, such as unreacted monomeror initiator, which can be toxic, at the end of the manufacturingprocess.

U.S. Pat. No. 4,540,602 (Motoyama, et al.) discloses a solid drugpulverized in a aqueous solution of a water-soluble high molecularsubstance using a wet grinding machine. However, Motoyama, et al. teachthat as a result of such wet grinding, the drug is formed into finelydivided particles ranging from 0.5 μm (500 nm) or less to 5 μm (5,000nm) in diameter.

EPO 275,796 describes the production of colloidally dispersible systemscomprising a substance in the form of spherical particles smaller than500 nm. However, the method involves a precipitation effected by mixinga solution of the substance and a miscible non-solvent for the substanceand results in the formation of non-crystalline nanoparticle. A somewhatmore involved solvent shift method is described in U.S. Pat. No.4,826,689 (Violanto) which produces uniform particles of drugs withdiameters ranging between 0.5 to 1.0 μm. Furthermore, precipitationtechniques for preparing particles tend to provide particlescontaminated with solvents. Such solvents are often toxic and can bevery difficult, if not impossible, to adequately remove topharmaceutically acceptable levels to be practical.

U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to1,000 nm containing a biologically or pharmaceutically active material.However, the particles comprise a crosslinked matrix of macromoleculeshaving the active material supported on or incorporated into the matrix.

U.S. Pat. No. 4,725,442 (Haynes) describes water insoluble drugmaterials solubilized in an organic liquid and incorporated inmicroencapsules of phospholipids. However, the toxic effects ofsolubilizing organic liquids is difficult to overcome. Other methods offormation of pharmaceutical drug microencapsule include:

a) Micronizing a slightly-soluble drug by subjecting a mixture of thedrug and a sugar or sugar alcohol to high-speed stirring comminution orimpact comminution (EP 411,629A) together with suitable excipients ordiluents. Such a method of encapsule formation does not lead to particlesize as small as obtained by milling.

b) Polymerization of a monomer in the presence of the active drugmaterial and a surfactant can lead to small-particle microencapsule(International Journal of Pharmaceutics, Vol. 52, pp. 101-108, 1989).This process, however, contains difficult-to-remove contaminants such astoxic monomers. Complete removal of such monomers can be expensive inmanufacturing scales.

c) Co-dispersion of a drug or a pharmaceutical agent in water withdroplets of carbohydrate polymer has been disclosed (U.S. Pat. No.4,713,249 and WO-84/00294). The major disadvantage of the procedure isthat in many cases, a solubilizing organic co-solvent is needed for theencapsulation procedure. Removal of traces of such harmful co-solventscan lead to expensive manufacturing processes.

Recently, many successful stable dispersions of nanoparticulate drug orpharmaceutical compositions have been prepared by wet milling of theagent in the presence of surfactants, polymers, block polymers, andoligomers as a mixture thereof as surface modifiers to producesterically stabilized dispersions of nanoparticulates with particlediameters less than 400 nm (U.S. Pat. No. 5,145,684, WPI 87-200422/29,EP 498,482 A2). This wet milling procedure still leads to theincorporation of solubilized heavy metals from the attrition of themilling media, which in many cases must be removed from the dispersionby tedious ion exchange procedures to formulate the final pharmaceuticalproduct.

It is noted that filed concurrently herewith are a) EK Docket No. 71870entitled, "Co-Microprecipitation of Nanoparticulate PharmaceuticalAgents With Crystal Growth Modifiers" by Pranab Bagchi et al; b) EKDocket No. 71871 entitled, "Microprecipitation of NanoparticulatePharmaceutical Agents Using Surface Active Material Derived from SimilarPharmaceutical Agents" by Pranab Bagchi et al; and c) EK Docket No.71872 entitled, "Microprecipitation of Micro-NanoparticulatePharmaceutical Agents" by Pranab Bagchi et al.

It would be desirable to provide stable dispersible drug orpharmaceutical agent particles in submicron size range which can bereadily prepared which do not appreciably flocculate or agglomerate dueto interparticle attraction forces, and do not require the presence of acrosslinked matrix, simultaneously providing enhanced bioavailability ofthe drug. Furthermore, it would be highly desirable that suchformulations do not involve removal of toxic residues such as toxicsolvents or heavy metal solubilizates that arise out of attrition of themilling media.

SUMMARY OF THE INVENTION

We have discovered a novel method of preparing stable dispersions ofdrugs and other pharmaceutical agents in the presence of a surfacemodifying and colloid stability enhancing surface active agent free oftrace of any toxic solvents or solubilized heavy metal inpurities by thefollowing procedural steps:

1. Dissolving the said pharmaceutical agent in aqueous base withstirring,

2. Adding above #1 formulation with stirring to a surface activesurfactant (or surface modifiers) solution to form a clear solution,and,

3. Neutralizing above formulation #2 with stirring with an appropriateacid solution. The procedure can be followed by:

4. Removal of formed salt by dialysis or diafiltration and

5. Concentration of dispersion by conventional means.

The process of this invention is illustrated in FIG. 1. The process ofthis invention produces dispersion of pharmaceutical agents withZ-average particle diameter less than 400 nm (as measured by photoncorrelation spectroscopy) that are stable in particle size upon keepingunder room temperature or refrigerated conditions. Such dispersions alsodemonstrate limited particle size growth upon autoclave-decontaminationconditions used for standard blood-pool pharmaceutical agents.

There can also be provided a pharmaceutical composition comprising theabove-described particles and a pharmaceutically acceptable carrierthereof. Such pharmaceutical composition is useful in a method oftreating mammals.

It is an advantageous feature that a wide variety of surface modifieddrug nanoparticles free of unacceptable contamination can be prepared inaccordance with this invention.

Another particularly advantageous feature of this invention is thatpharmaceutical compositions are provided exhibiting unexpectedly highbioavailability.

Still another advantageous feature of this invention is thatpharmaceutical compositions containing poorly water soluble drugsubstances are provided which are suitable for intravenousadministration techniques.

In other preferred embodiments of this invention, step 3 (FIG. 1) can becarried out in semicontinuous, continuous batch, or continuous methodsat constant flow rates of the reacting components in computer-controlledreactors or in tubular reactors where reaction pH can be kept constantusing pH-stat systems, as will be described in "Description of PreferredEmbodiments." Advantages of such preferred modifications of thisinvention are clear in that they provide cheaper manufacturingprocedures for largescale production of nanoparticulate dispersionsystems.

Another advantage of the invention is that unlike milled dispersion, thefinal product is free of heavy metal contaminants arising from themilling media that must be removed due to their toxicity before productis formulated.

A further advantage of the method is that unlike solvent precipitation,the final product of this invention is free of any trace of tracesolvents that may be toxic and must be removed by expensive treatmentsprior to final product formulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Schematic for the microprecipitation of nanoparticulatepharmaceutical agents.

FIG. 2 Schematic for large-scale manufacture of nanoparticulatepharmaceutical agents.

FIG. 3 Schematic for large-scale manufacture of nanoparticulatepharmaceutical agents using base hydrolyzable surface modifyingcompounds.

FIG. 4 Schematic for large-scale manufacture of nanoparticulatepharmaceutical agents using base hydrolyzable surfactants by continuousdirect mixing.

FIG. 5 Schematic for the small-scale pH-controlled microprecipitationdevice.

FIG. 6 Schematic for the larger-scale pH-controlled microprecipitationdevice.

FIG. 7 Schematic for alternate small-scale precipitation ofpharmaceutical agents.

FIG. 8 Schematic of continuous tubular microprecipitation device of thisinvention.

FIG. 9 Cryo-transmission electron photomicrograph of nanoparticulateX-ray contrast agent "X" as prepared by the method of this invention inExample 1.

DESCRIPTION OF PREFERRED EMBODIMENTS

This invention is based partly on the discovery that pharmaceuticalagent particles having an extremely small effective average particlesize can be prepared by homogeneous nucleation and precipitation in thepresence of a surface modifier, and that such particles are stable anddo not appreciably flocculate or aggregate due to interparticleattractive force and can be formulated into pharmaceutical compositionsexhibiting unexpectedly high bioavailability. While the invention isdescribed herein primarily in connection with its preferred utility,i.e., with respect to nanoparticulate drug substances for use inpharmaceutical compositions, it is also believed to be useful in otherapplications such as the formulation of particulate cosmeticcompositions and the preparation of particulate dispersions for use inimage and magnetic recording elements.

The particles of this invention comprise a pharmaceutical agentsubstance. The said agent substance exists as a discrete, crystallinephase. The crystalline phase differs from a non-crystalline or amorphousphase which results from precipitation techniques, such as described inEPO 275,796 cited above.

The invention can be practiced with a wide variety of pharmaceuticalagent substances. The said agent substance preferably is present in anessentially pure form. The drug substance must be poorly soluble anddispersible in at least one liquid medium. By "poorly soluble" it ismeant that the said substance has a solubility in the liquid dispersionmedium of less than about 10 mg/mL, and preferably of less than about 1mg/mL. A preferred liquid dispersion medium is water. However, theinvention can be practiced with other liquid media in which apharmaceutical agent is poorly soluble an dispersible including, forexample, aqueous salt solutions, safflower oil, and solvents such asethanol, t-butanol, hexane, and glycol. The pH of the aqueous dispersionmedia can be adjusted by techniques known in the art.

Suitable pharmaceutical agents can be selected from a variety of knownclasses of drugs including, for example, analgesics, anti-inflammatoryagents, anthelmintics, anti-arrhythmic agents, antibiotics (includingpenicillins), anticoagulants, antidepressants, antidiabetic agents,antiepileptics, antihistamines, antihypertensive agents, antimuscarinicagents, antimycobacterial agents, antineioplastic agents,immunosuppressants, antithyroid agents, antiviral agents, anxiolyticsedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptorblocking agents, blood products and substitutes, cardiac inotropicagents, contrast media, corticosteroids, cough suppressants(expectorants and mucolytics), diagnostic agents, diagnostic imagingagents, diuretics, dopaminerigics (antiparkinsonian agents),haemostatics, immuriological agents, lipid regulating agents, musclerelaxants, parasympathomimetics, parathyroid calcitonin andbiphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones(including steroids), anti-allergic agents, stimulants and anoretics,sympathomimetics, thyroid agents, vasodilators and xanthines. Preferreddrug substances include those intended for oral administration andintravenous administration. A description of these classes ofpharmaceutical agents and a listing of species within each class can befound in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, ThePharmaceutical Press, London, 1989, the disclosure of which is herebyincorporated by reference in its entirety. The drug substances arecommercially available and/or can be prepared by techniques known in theart.

The particles of this invention contain a discrete phase of a saidsubstance as described above having a surface modifier adsorbed on thesurface thereof. Useful surface modifiers are believed to include thosewhich physically adhere to the surface of the drug substance but do notchemically bond to the drug.

Suitable surface modifiers (the term "surface modifiers" is usedinterchangeably with "surfactants" can preferably be selected from knownorganic and inorganic pharmaceutical excipients. Such excipients includevarious polymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants. Representative examples of excipients include gelatin,casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth,stearic acid, benzalkonium chloride, calcium stearate, glycerylmonostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, polyoxyethylene alkyl ethers, e.g., ethylene castor oilderivatives, polyoxyethylene sorbitan fatty acid esters, e.g., thecommercially available Tweens, polyethylene glycols, polyoxyethylenestearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, non-crystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, andpolyvinylpyrrolidone (PVP). Most of these excipients are described indetail in the Handbook of Pharmaceutical Excipients, published jointlyby the American Pharmaceutical Association and The PharmaceuticalSociety of Great Britain, the Pharmaceutical Press, 1986, the disclosureof which is hereby incorporated by reference in its entirety. Thesurface modifiers are commercially available and/or can be prepared bytechniques known in the art.

Particularly preferred surface modifiers include polyvinyl pyrrolidone,Pluronic F68 and F108, which are block copolymers of ethylene oxide andpropylene oxide, Tetronic 908, which is a tetrafunctional blockcopolymer derived from sequential addition of ethylene oxide andpropylene oxide to ethylenediamine, dextran, lecithin, Aerosol OT, whichis a dioctyl ester of sodium sulfosuccinic acid, available from AmericanCyanamid, Duponol P, which is a sodium lauryl sulfate, available fromDuPont, Triton X200, which is an alkyl aryl polyether sulfonate,available from Rohm and Haas, Tween 80, which is a polyoxyethylenesorbitan fatty acid ester, available from JCI Specialty Chemicals, andCarbowax 3350 and 934, which are polyethylene glycols available fromUnion Carbide. Surface modifiers which have found to be particularlyuseful include polyvinylpyrrolidone, Pluronic F-68, and lecithin.

The surface modifier is adsorbed on the surface of the pharmaceuticalagent in an amount sufficient to maintain an effective average particlesize of less than about 400 nm. The surface modifier does not chemicallyreact with the drug substance or itself. Furthermore, the individuallyadsorbed molecules of the surface modifier are essentially free ofintermolecular crosslinkages.

As used herein, particle size refers to a number average particle sizeas measured by conventional particle size measuring techniques wellknown to those skilled in the art, such as sedimentation field flowfractionation, photon correlation spectroscopy, or disk centrifugation.By "an effective average particle size of less than about 400 nm" it ismeant that at least 90% of the particles have a weight average particlesize of less than about 400 nm when measured by the above-notedtechniques. In preferred embodiments of the invention, the effectiveaverage particle size is less than about 250 nm. In some embodiments ofthe invention, an effective average particle size of less than about 100nm has been achieved. With reference to the effective average particlesize, it is preferred that at least 95% and, more preferably, at least99% of the particles have a particle size less than the effectiveaverage, e.g., 400 nm. In particularly preferred embodiments,essentially all of the particles have a size less than 400 nm. In someembodiments, essentially all of the particles have a size less than 250nm. When photon correlation spectroscopy (PCS) is used as the method ofparticle sizing the average particle diameter is the Z-average particlediameter known to those skilled in the art.

Additional surface modifier may be added to the dispersion afterprecipitation. Thereafter, the dispersion can be mixed, e.g., by shakingvigorously. Optionally, the dispersion can be subjected to a sonicationstep, e.g., using an ultrasonic power supply. For example, thedispersion can be subjected to ultrasonic energy having a frequency of20-80 kHz for a time of about 1 to 120 seconds.

The relative amount of agent substance and surface modifier can varywidely and the optimal amount of the surface modifier can depend, forexample, upon the particular drug substance and surface modifierselected, the critical micelle concentration of the surface modifier ifit forms micelies, etc. The surface modifier preferably is present in anamount of about 0.1-10 mg per square meter surface area of the drugsubstance. The surface modifier can be present in an amount of 0.1-90%,preferably 20-60% by weight based on the total weight of the dryparticle.

The resulting dispersion of this invention is stable and consists of theliquid dispersion medium and the above-described particles. Thedispersion of surface modified drug nanoparticles can be spray-coatedonto sugar spheres or onto a pharmaceutical excipient in a fluid-bedspray coater by techniques well-known in the art.

In a preferred embodiment, the above procedure is followed with step 4which comprises removing the formed salts by diafiltration or dialysis.This is done in the case of dialysis by standard dialysis equipment andby diafiltration using standard diafiltration equipment known in theart. Preferably, the final step is concentration to a desiredconcentration of the agent dispersion. This is done either bydiafiltration or evaporation using standard equipment known in this art.

Pharmaceutical compositions according to this invention include theparticles described above and a pharmaceutically acceptable carriertherefore. Suitable pharmaceutically acceptable carriers are wellknownto those skilled in the art. These include nontoxic physiologicallyacceptable carriers, adjuvants or vehicles for parenteral injection, fororal administration in solid or liquid form, for rectal administration,and the like. A method of treating a mammal in accordance with thisinvention comprises the step of administering to the mammal in need oftreatment an effective amount of the above-described pharmaceuticalcomposition. The selected dosage level of the agent substance fortreatment is effective to obtain a desired therapeutic response for aparticular composition and method of administration. The selected dosagelevel therefore, depends upon the particular drug substance, the desiredtherapeutic effect, on the route of administration, on the desiredduration of treatment and other factors. As noted, it is a particularlyadvantageous feature that the pharmaceutical compositions of thisinvention exhibit unexpectedly high bioavailability as illustrated inthe examples which follow. Furthermore, it is contemplated that the drugparticles of this invention provide more rapid onset of drug action anddecreased gastrointestinal irritancy.

It is contemplated that the pharmaceutical compositions of thisinvention will be particularly useful in oral and parenteral, includingintravenous, administration applications. It is expected that poorlywater soluble drug substances, which prior to this invention, could nothave been administered intravenously, may be administered safely inaccordance with this invention. Additionally, drug-substances whichcould not have been administered orally due to poor bioavailability maybe effectively administered in accordance with this invention.

While applicants do not wish to be bound by theoretical mechanisms, itis believed that the surface modifier hinders the flocculation and/oragglomeration of the particles by functioning as a mechanical or stericbarrier between the particles, minimizing the close, interparticleapproach necessary for agglomeration and flocculation. Alternatively, ifthe surface modifier has ionic groups, stabilization by electrostaticrepulsion may result. It was surprising that stable drug particles ofsuch a small effective average particle size and free of unacceptablecontamination could be prepared by the method of this invention.

Representative illustrative species of substances useful in the practiceof this invention include the X-ray contrast agent Xethyl-3,5-diacetoamido-2,4,6-triiodobenzoate or ##STR1##

Other illustrative examples of species of pharmaceutical contrast agentsinclude the following compounds. ##STR2##

In the above structures, R can be OR' ##STR3## wherein R' is alkyl, andR² and R³ are independently H or alkyl. Each alkyl group canindependently contain from 1-20, preferably 1-8, and more preferably,1-4 carbon atoms. The alkylene group preferably contains from 1-4carbons atoms such as methylene, ethylene, propylene and the like,optionally substituted with for example an alkyl group, such as methyland ethyl.

Particularly preferred contrast agents include the ethyl ester ofdiatrizonic acid, i.e., ethyl-3,5-diacetamido-2,4,6-triiodobenzoate,also known as ethyl-3,5-bis(acetylamino)-2,4,6-triodobenzoate or tehyldiatrizoate, having the structural formula A above wherein R=--OCH₂ CH₃the ethyl glycolate ester of diatrizoic acid, i.e.,ethyl(3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy)acetate, also knownas ethyl diatrizoxyacetate, having the structural formula A abovewherein ##STR4## andethyl-2-(3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy)butyrate, alsoknown as ethyl-2-diatrizoxybutyrate, having the structural formula Aabove wherein ##STR5##

In addition, it is expected that the invention can be practiced inconjunction with the water insoluble iodinated carbonate estersdescribed in PCT/EP90/00053.

The above described X-ray contrast agents are known compounds and/or canbe prepared by techniques known in the art. For example, water-insolubleesters and terminal amides of acids such as the abovedescribed iodinatedaromatic acids can be prepared by conventional alkylation or amidationtechniques known in the art. The above-noted acids and other acids whichcan be used as starting materials are commercially available and/or canbe prepared by techniques known in the art. The examples which followcontain illustrative examples of known synthetic techniques.

The particles useful in the practice of this invention include a surfacemodifier. Surface modifiers useful herein physically adhere to thesurface of the X-ray contrast agent but do not chemically react with theagent or itself. Individually adsorbed molecules of the surface modifierare essentially free of intermolecular cross- linkages.

It is to be noted that agents (therapeutic or diagnostic) that aresuitable for this invention must be soluble but remain relativelyunhydrolyzed in aqueous alkaline solutions. Compounds described in U.S.Pat. Nos. 5,264,610, 5,260,478 (Bacon) and (application) PRF-469/92(Bacon, et al.) that are unhydrolyzable in aqueous alkaline solutionsare also included herein by reference as agents suitable for thepractice of this invention.

The X-ray contrast agent can be an iodinated compound. The iodinatedcompound can be aromatic or nonaromatic. Aromatic compounds arepreferred. The iodinated compound can comprise one, two, three, or moreiodine atoms per molecule. Preferred species contain at least two, andmore preferably, at least three iodine atoms per molecule. The iodinatedcompounds selected can contain substituents that do not impartsolubility to the compound, such as, for example, alkylureido,alkoxyacylamido, hydroxyacetamido, butyrolactamido, succinimido,trifluoroacetamido, carboxy, carboxamido, hydroxy, alkoxy, acylamino,and the like substituents.

A preferred class of contrast agents includes various esters and amidesof iodinated aromatic acids. The esters preferably are alkyl orsubstituted alkyl esters. The amides can be primary or secondary amides,preferably alkyl or substituted alkyl amides. For example, the contrastagent can be an ester or amide of a substituted triiodobenzoic acid suchas an acyt, carbamyl, and/or acylmethyl substituted triiodobenzoic acid.Illustrative representative examples of iodinated aromatic acidsinclude, but are not limited to, diatrizoic acid, metrizoic, iothalamicacid, trimesic acid, ioxaglic acid (hexabrix), ioxitalamic acid,tetraiodoterephthalic acid, iodipamide and the like. It is contemplatedthat poorly soluble derivatives of iodamide and iopyrol can be usedherein.

The invention can also be practiced with poorly soluble derivatives,e.g., ester and ether derivatives, of hydroxylated nonionic X-raycontrast agents. Illustrative nonionic contrast agents include, but arenot limited to, metrizamide; ioglunide; iopamidol; iopromide;iogulamide; iohexol, and other compounds described in U.S. Pat. No.4,250,113; ioversol, and other compounds described in U.S. Pat. No.4,396,598; nonionic triiodinated compounds, such as described inInvestigative Radiology, Vol. 19, July-August 1984; and nonionic dimers,such as described in Radiology, 142: 115-118, January 1982. Theinvention can be practiced with poorly soluble derivatives ofiodomethane sulfonamides, iodinated aromatic glucoanilides,2-ketogulonamides, reversed amides, peptides, carbamates, esters,glycoside and glucose derivatives, benzamide derivatives,isophthalamides, bis compounds, and bispolyhydroxylated acylamides, suchas described in Volume 73 of the Handbook of Experimental Pharmacology,entitled Radiocontrast Agents, edited by M. Sovak, 1984,Springer-Verlag, Berlin, pages 56-73.

Many of the iodinated molecules described above, if in monomeric form,can also be prepared as dimers (sometimes referred to as bis compounds),trimers (sometimes referred to as tris compounds), etc., by techniquesknown in the art. It is contemplated that this invention can bepracticed with poorly soluble-iodinated compounds in monomeric, dimeric,trimeric and polymeric forms. Representative illustrative compounds aredescribed by Sovak, cited above, pages 40-53.

Methods of Performing the Invention

The process of this invention involves a method of preparing stabledispersions of drugs and other pharmaceutical agents in the presence ofa surface modifying and colloid stability-enhancing surface active agentfree of trace any toxic solvents or solubilized heavy metal impuritiesby the following procedural steps.

1. Dissolving the said pharmaceutical agent in aqueous base withstirring,

2. Adding above #1 formulation, with stirring, to a surface activesurfactant (or surface modifiers) solution to form a clear solution and,

3. Neutralizing above formulation, with stirring, #2 with an appropriateacid solution and optionally,

4. Removal of salts with dialysis or diafiltration and

5. Concentration of dispersion by conventional means.

The process of this invention is illustrated in FIG. 1. The process ofthis invention produces dispersion of photographic agent with averageparticle size, less than 400 nm in diameter that are stable in particlesize upon keeping under room temperature or refrigerated conditions.Such dispersions also demonstrate limited particle size growth uponautoclave decontamination conditions used for standard blood-poolpharmaceutical agents.

This invention can also be performed in semicontinuous, continuous, orcontinuous batch methods. Such methods provide numerous advantages overprior processes of forming dispersions of pharmaceutical agents. Theinvention provides continuous or semicontinuous methods in which theparticle size of the formed dispersions will be reproducible from run torun. Shutdowns of the system can be accomplished with minimum waste orgrowth of particle size. These and other advantages of the inventionwill become apparent from the detailed description below.

The schematic of FIG. 2 illustrates apparatus 80 for performing theprocess of the invention. The apparatus is provided with high puritywater delivery lines 12. Tank 14 contains a solution 11 of surfactantand high purity water. Jacket 15 on tank 14 regulates the temperature ofthe tank. Surfactant enters the tank through line 16. Tank 18 contains apharmaceutical agent solution 19. Jacket 17 controls the temperature ofmaterials in tank 18. The tank 18 contains a port for delivery of thepharmaceutical agent entering through manhole 20, a base material suchas aqueous sodium hydroxide solution entering through line 22. Thesolution is maintained under agitation by the mixer 26. Tank 81 containsacid solution 25 such as propionic acid solution entering through line30. The tank 81 is provided with a heat jacket 28 to control thetemperature, although with the acids normally used, it is not necessary.In operation, the acid solution is fed from tank 81 through line 32 tomixer 34 via the metering pump 86 and flow meter 88. A pH sensor 40senses the acidity of the dispersion as it leaves mixer 34 and allowsthe operator to adjust the acid pump 86 to maintain the proper pH in thedispersion exiting the mixer 34. The pharmaceutical agent 19 passesthrough line 42, metering pump 36, flow meter 38, and joins thesurfactant solution in tank 14. In tank 14, the alkaline pharmaceuticalagent is mixed with the surfactant solution and is pumped using pump 29and flow meter 31 into the mixing chamber 34.

The particles are formed in mixer 34 and exit through pipe 48 into theultrafiltration tank 82. In the preferred process, tank 82, thedispersion 51 is held while it is washed by ultrafiltration membrane 54to remove the salt from solution and adjust the material to the properwater content for makeup at the proper concentration. The source of highpurity water is purifier 56. Agitator 13 agitates the surfactantsolution in tank 14. Agitator 27 agitates the acid solution in tank 81.The generated salts are removed during the ultrafiltration processthrough permeate (filtrate) stream 58.

In some instances, the suitable surface modifier is the surface activeagent in an ester that may be base hydrolyzable. An example of suchsurfactant is Aerosol A102 or Aerosol A103, manufactured by AmericanCyanamid. ##STR6##

During small-scale laboratory precipitation scheme described in FIG. 1,preparation time is short enough such that hydrolysis of the surfactantin alkaline solution is virtually undetectable. However, duringmanufacturing, mixing and holding time could extend to 1-2 hours. Insuch case, hydrolysis of the surfactant is substantial and needs to beeliminated by reducing the contact time of the surfactant with thealkali. To accomplish this, the following manufacturing schemes areadopted.

In the following embodiment of the invention, the alkalinepharmaceutical agent solution is mixed with the surfactant solutioncontinuously and neutralized within less than a second of mixing in acontinuous reactor with acid solution to eliminate surfactanthydrolysis.

The schematic of FIG. 3 illustrates apparatus 10 for performing theprocess of the invention. The apparatus is provided with high puritywater delivery lines 12. Tank 14 contains a solution 11 of surfactantand high purity water. Jacket 15 on tank 14 regulates the temperature ofthe tank. Surfactant enters the tank through line 16. Tank 18 contains apharmaceutical agent solution 19. Jacket 17 controls the temperature ofmaterials in tank 18. The tank 18 contains a port for delivery of thepharmaceutical agent entering through manhole 20, a base material suchas aqueous sodium hydroxide solution entering through line 22. Thesolution is maintained under agitation by the mixer 26. Tank 81 containsacid solution 25 such as propionic acid entering through line 30. Thetank 81 is provided with a heal jacket 28 to control the temperature,although with the acids normally used, it is not necessary. Inoperation, the acid is fed from tank 81 through line 32 to mixer 34 viathe metering pump 86 and flow meter 88. A pH sensor 40 senses theacidity of the dispersion as it leaves mixer 34 and allows the operatorto adjust the acid pump 86 to maintain the proper pH in the dispersionexiting the mixer 34. The pharmaceutical agent 19 passes through line42, metering pump 36, flow meter 38, and joins the surfactant solutionin line 44 at the T fitting 46. The particles are formed in mixer 34 andexit through pipe 48 into the ultrafiltration tank 82. In tank 82, thedispersion 51 is held while it is washed by ultrafiltration membrane 54to remove the salt from solution and adjust the material to the properwater content for makeup at the proper concentration. The source of highpurity water is purifier 56. Agitator 13 agitates the surfactantsolution in tank 14. Agitator 27 agitates the acid solution in tank 81.The generated salts are removed during the ultrafiltration processthrough permeate (filtrate) stream 58.

In some cases, the alkaline pharmaceutical agent, the surfactantsolution, and the acid solution may be directly and continuously mixedin the continuous mixer to obtain nanoparticulate dispersions. In such acase, the following manufacturing scheme is adopted.

The apparatus 70 schematically illustrated in FIG. 4 is similar to thatillustrated in FIG. 3 except that the acid solution in pipe 32, thesurfactant solution in pipe 44, and the pharmaceutical agent solution inpipe 42 are directly led to mixing device 34. Corresponding items inFIG. 3 and FIG. 4 have the same numbers. In this system, all mixingtakes place in the mixer 34 rather than joining of the surfactantsolution and the pharmaceutical agent solution in the T connectionimmediately prior to the mixer as in the FIG. 3 process.

The previously described methods of this invention find their mostpreferred use in large-scale production such as in a continuouscommercial process. However, preparation of dispersions in pH-controlledconditions can also be practiced on a smaller and/or slower scale in asemicontinuous or continuous manner. The devices of FIGS. 5 and 6illustrate equipment that is in accordance with the invention forsmaller scale production. The device of FIG. 5 was designed forcontinuous pH-controlled precipitation of dispersions. The apparatus 90of FIG. 5 provides a continuous means for precipitation ofnanoparticulate dispersions. Container 92 is provided with an aqueoussurfactant solution 94. Container 96 is provided with an acid solution.Container 100 contains a basic solution 102 of the pharmaceutical agent.Container 104 provides a mixing and reacting chamber where thedispersion formation takes place. Container 106 is a collector for thedispersed suspensions 158. In operation, the surfactant solution 94 ismetered by pump 108 through line 110 into the reactor vessel 104. At thesame time, the basic pharmaceutical agent solution is metered by pump112 through line 114 into the reactor 104 at a constant predeterminedrate. The solutions are agitated by stirrer 116, and acid 98 is meteredby pump 118 through line 121 into the reactor 104 to neutralize thesolution. The pumping by metering pump 118 is regulated by controller120. Controller 120 is provided with a pH sensor 122 that senses the pHof the dispersion 124 in reactor 104 and controls the amount and therate of the addition of acid 98 added by pump 118 to neutralize thecontent of the reaction chamber. The drive for stirrer 116 is 126. Therecorder 130 constantly records the pH of the solution to provide ahistory of the dispersion 124. Metering pump 132 withdraws thedispersion solution from reactor 104 and delivers it to the container106 using pump 132 and line 150 where it may exit from the outlet 134.In a typical precipitation, there is a basic pharmaceutical agentsolution 102, sodium hydroxide solution, and the surfactant. Thesurfactant is in water, and the neutralizing acid is an aqueous solutionof acetic or propionic acid. The reaction chamber has a capacity ofabout 800 mL. Pharmaceutical agent solution tank 100 has a capacity ofabout 2500 mL. The surfactant solution tank 92 has a capacity of about5000 mL. The acid solution tank has a capacity of about 2500 mL, and thedispersion collection tank has a capacity of about 10,000 mL. Thetemperature is controlled by placing the four containers 92, 96, 104,and 100 in a bath 136 of water 138 whose temperature can be regulated toits temperature up to 100° C. Usually, precipitation is carried out at25° C. The temperature of the bath 138 is controlled by a steam and coldwater mixer (not shown). The temperature probe 140 is to sense thetemperature of the reactor. This is necessary for correct pH reading.The neutralization of the basic pharmaceutical agent solution in thereaction chamber 104 by the proportionally controlled pump 118 whichpumps in acid solution 98 results in control of pH throughout the run to±0.2 of the set pH value which is usually about 6.0.

FIG. 6 schematically illustrates a semicontinuous system for formingnanoparticulate dispersions of pharmaceutical materials. Identical itemsare labeled the same as in FIG. 5. Because of reduced scale, the sizesof acid kettle 96 and the pharmaceutical agent kettle 100 are smaller(about 800 mL each). In the system of FIG. 6, the reactor 104 isinitially provided with an aqueous surfactant solution. In this ispumped a basic solution of photographic agent 102 through pipe 114. 112is a pH sensor that, working through controller 120, activates pump 118to neutralize the dispersion to a pH of about 6 by pumping acetic acid98 through metering pump 118 and line 121 to the reactor 104. Reactor104 must be removed, dumped, and refilled with the aqueous surfactantsolution in order to start a subsequent run.

The base used to solubilize the photographic agent could be any strongalkali as NH₄ OH, NaOH, KOH, LiOH, RbOH, or CsOH, or organic bases asamines such as trialkyl amines or pyridine, etc.

The acids used for neutralization in this invention preferably could beany weak acids such as formic, acetic, propionic, butyric acids, etc.,or in some cases, mineral acids such as HCl, H₂ SO₄, HNO₃, HClO₄, may bepreferred.

Other modifications of this invention could be performed according tothe processes described in other patents of Bagchi, et al., such as U.S.Pat. No. 4,933,270; 4,970,131; 4,900,431; 5,013,640; 5,089,380;5,091,296; 5,104,776; 5,135,884; 5,158,863; 5,182,189; 5,185,230;5,264,317; 5,279,931; 5,358,831 and are hereby incorporated herein byreference.

Another preferred modification of the precipitation device of thisequipment, 700, of this invention is shown in FIG. 7.

FIG. 7 schematically depicts a batch system for precipitatingcrystalline nanoparticulate pharmaceutical agent suspensions. Thereactor 701 is initially provided with an aqueous solution ofsurfactant, or a surface modifier and pH buffer. The reactor is equippedwith a magnetic stirring bar 702, a temperature probe 703, and a pHsensor 704. The revolutions of the magnetic stirring bar are maintainedat a medium-high level, as controlled by a magnetic plate regulator 705.A strongly basic, particle-free aqueous solution of the pharmaceuticalagent is delivered by a pump, 706, with a flow rate control, via tubing707, to the reactor. Simultaneously, an aqueous acid solution isdelivered to the reactor by a pump 708 with a flow rate control viatubing 709. The flow rate of both streams, their concentration, and theduration of their subsurface delivery are carefully selected in such amanner that the final pH is restricted between 3.0 and 7.0, and thefinal concentration of the suspension is between 0.5% to 10%. Containers710 and 711 hold the pharmaceutical agent solution and acid solution,respectively.

In another preferred embodiment of the invention continuousprecipitation may be carried out in a tubular reactor 800 of FIG. 8.

The neutralization reaction takes place in a tubular reactor, whichconsists of a tubing or pipe 801 equipped with a static mixer 802. Theinlet section of the tubular reactor allows for an influx of threestreams through three connectors 803, 804, and 805. Initially, thetubular reactor is supplied with a stream of an aqueous carrier solutionof surfactant and pH adjusting buffer, by a pump 806, with a flow ratecontrol, via tubing 807, and the connector 803. A strongly basic,particle-free aqueous solution of the pharmaceutical agent is deliveredby a pump 808 with a flow rate control, via tubing 809 and the connector804, to the tubular reactor. Simultaneously, an aqueous acid solution isdelivered to the reactor by a pump with a flow rate control 810, viatubing 811 and the connector 805. The flow rate of the influx streamsand their concentration are selected in such a manner that the final pHis less than 7.0, and preferably is between 3.0 and 7.0, and the finalconcentration of the suspension is between 0.5% to 10%. Containers 812,813, 814, and 815 hold carrier solution, pharmaceutical agent solution,acid solution, and the product suspension, respectively. The totallength of the tubular reactor is such that the reaction is completedbefore the suspension reaches the outlet of the reactor, at the flowrates of the influx streams and the diameter of the reactor used. In analternate embodiment of the above apparatus, only two inlet streams aresimultaneously delivered to the tubular reactor. The connector 803 isplugged off, and the pump 806 is not shut off. Since the carriersolution is not used, the aggregate volumetric flow rate of the tworeactant streams is higher than that typically employed in thethree-stream configuration described above.

The invention is illustrated in the following examples.

EXAMPLE 1

Pharmaceutical agent solution of X-ray contrast agent, X, was preparedaccording to the method of this invention as follows. Five grams ofcompound X was added to 5 g of distilled water and 11.15 g of 20% NaOHsolution. The mixture according to step 1 of FIG. 1 was dissolved byheating to 56° C. and then the clear solution was cooled to roomtemperature. A surfactant surface modifier was prepared by dissolving2.1 g of a 60% solution of Polystep B23 (Stephan) and 0.1 g of AerosolOT in 125 g of distilled water. The alkaline drug solution in step 2 ofFIG. 1 of this invention was added to the surfactant solution. ##STR7##

According to step 3 of FIG. 1 of this invention the aqueous alkalinedrug solution was neutralized using 75 mL of 15% aqueous propionic acidsolution to form the nanoparticulate slurry of contrast agent X. Theslurry was continuously dialyzed for 24 hr against distilled water toremove salts.

A cryo-transmission electron micrographic picture of the formeddispersion is shown in FIG. 9. The particles of the nanoparticulatedispersion were found to be thin platelets with a range of sizes. TheZ-average particle size of the dispersion system was determined byphoton correlation spectroscopy (PCS) to be 290 nm. The dispersion wassubjected to an autoclave treatment at 120° C. for 25 minutes todetermine effect of sterilization. After autoclaving, the Z-averageparticle diameter was found to be 350 nm, indicating some growth of theparticle size. The zeta potential of the original dispersion particleswas also determined by photon correlation spectroscopy to be -31 mV. Thephysical characteristics of this dispersion is shown in Table I.

EXAMPLE 2

The nanoparticulate drug dispersion of this example was prepared by muchthe same manner as that of Example 1 using the steps of FIG. 1. Thevarious solution compositions were as follows:

    ______________________________________                                        X-ray Contrast Agent "X"                                                                          -20 g                                                     Distilled Water     -20 g                                                     20% NaOH solution   -45 g                                                     ______________________________________                                    

Dissolved at 50° C. and cooled to room temperature.

Aqueous surfactant solution:

    ______________________________________                                        Polyvinyl Pyrolidone (PVP)                                                                           -10     g                                              Aerosol OT             -5      g                                              Distilled Water        -500    g                                              ______________________________________                                    

The alkaline drug and surfactant solution was neutralized with 300 g of15% propionic acid solution to form the nanoparticulate dispersion. Theformed dispersion was continuously dialyzed for 24 hr to remove theformed salt. The particle diameter of the formed dispersion was measuredby PCS and the Z-average diameter was determined to be 247 nm. Afterautoclaving under the same conditions, as indicated in Example 1, theZ-average particle diameter by PCS was found to be 311 nm. The zetapotential of the original dispersion was determined by PCS to be -29 mV.Physical characteristics of the dispersion are also indicated in TableI. Cryo-transmission electron microscopy (not shown), indicated theformed dispersion particles appeared similar to that of FIG. 9.

EXAMPLE 3

This nanoparticulate dispersion of x-ray contrast agent "X" was preparedexactly by the same manner as that of Example 2 except it was performedin a scale that is 1/4of that of Example 2, and also contained halfproportion of the surface modifiers PVP and Aerosol OT compared to thatin Example 2 in comparison with the amount of X-ray contrast agent "X."The various physical parameters of the dispersion were as follows:

Particle diameter (PCS) after preparation-240 nm (Z-average)

Particle diameter (PCS) after autoclaving-298 nm (Z-average)

Zeta potential (PCS) of initial dispersion-30 mV

Cryo-transmission electron micrographs indicated that the dispersionparticle were similar to those of Example 1. The physical data are alsolisted in Table I.

EXAMPLE 4

The nanoparticulate dispersion of the contrast agent "X" of this examplewas prepared by much the same manner as that of Example 1, using thesteps indicated in FIG. 1. The various solution compositions were asfollows:

Aqueous alkaline drug solution:

    ______________________________________                                        X-ray Contrast Agent "X"                                                                             -5      g                                              Distilled Water        -5      g                                              20% NaOH Solution      -11.15  g                                              ______________________________________                                    

Dissolved at 55° C. and cooled to room temperature.

Aqueous surfactant solution:

    ______________________________________                                        Aerosol OT             -0.1    g                                              Tetronic T908 (BASF Corp.)                                                                           -1.165  g                                              Distilled Water        -125    g                                              ______________________________________                                    

The alkaline drug and surfactant solution was neutralized with 75 cc of15% propionic acid solution to form the nanoparticulate dispersion. Thedispersion was dialyzed continuously against distilled water to removeformed salt. Cryo-transmission photo electron micrographs indicated thatthe dispersion particles appeared very similar to those of Example 1.The various physical parameters of the dispersion were as follows:

Particle diameter (PCS) after preparation-274 nm (Z-average)

Particle diameter (PCS) after autoclaving-826 nm (Z-average)

Zeta Potential (PCS)-20 mV

The physical data are also listed in Table I.

Even though none of the dispersions were concentrated, it is well-knownthat these dispersions can be concentrated to desired concentrations bydiafiltration, evaporation in a rotational vacuum evaporator or byevaporation in the dialysis bag in a well-exhausted hood. However, thisthird method is slow and may take up to 5 days to obtain concentrationsof 10-18% of the X-ray contrast agent. All nanoparticulate dispersionsappear to have Z-average diameters small enough for use in blood-pooldiagnostic procedures and also for oral procedures.

                  TABLE I                                                         ______________________________________                                        Physical Characteristics of Microprecipitated                                 Nanoparticulate Dispersions of Compound X                                                  PCS Particle                                                                  Diameter, Z-Av.                                                               nm           Zeta                                                Ex-   Surface              After    Potential                                 ample Modifiers    Initial Autoclaving                                                                            (mV) by PCS                               ______________________________________                                        1     Polystep B23 290     356      -31                                       2     Aerosol OT/PVP                                                                             247     311      -29                                       3     Aerosol      240     298      -30                                             OT/PVP.sup.1                                                            4     Aerosol OT/T908                                                                            274     826      -20                                       Con-  Aerosol      278     448      --                                        trol 5                                                                              OT/908 + PEG                                                            ______________________________________                                         .sup.1 Half surface modifiers compared to Example 2.                     

Control 5: Wet-Milled Dispersion

A wet-milled nanoparticulate dispersion of compound "X" was alsoprepared by milling procedure described in European Patent Application0,498,482 A2 using Tetronic T908 as described in Example 1 of EP0,498,482 A2. The dispersion was further stabilized with the addition ofpolyethylene glycol at 0.67 g per g of compound "X." The milleddispersion produced an initial Z-average particle diameter by PCS of 278nm. However, upon incubation in an autoclave grew to 448 nm, underconditions described in Example 1. It is seen in Table I, that allmicroprecipitated dispersions of the instant invention have particlesize similar to known pharmaceutical dispersion prepared by millingexcept that the microprecipitated particle do not have anycontaminations from residual solvents as from attrition of the millingmedia (beads).

The invention has been described in detail with reference to preferredembodiments thereof, but it will be understood that various variationsand modifications can be effected within the spirit and scope of theinvention.

We claim:
 1. A process of forming nanoparticulate dispersions ofpharmaceutical agents comprising:first step of dissolution of thepharmaceutical agent in aqueous base, a second step of adding to it anaqueous solution of one or more surface modifiers and a third step ofneutralizing the formed alkaline solution with an acid to form adispersion.
 2. The process of claim 1 wherein the pharmaceutical agentis selected from:therapeutic agent and diagnostic agent.
 3. The processof claim 1 wherein the nanoparticulate dispersion is characterized by aZ-average particle diameter less than 400 nm as measured by photoncorrelation spectroscopy.
 4. The process of claim 1 wherein the base isselected from any one or a combination of the following:NaOH KOH CsOHtrialkyl amines and pyridine.
 5. The process of claim 1 wherein theneutralizing acid is selected from:a weak acid and a strong acid.
 6. Theprocess of claim 1 wherein the neutralizing acid is selected from one ofthe following:HCl HNO₃ HClO₄ H₂ SO₄ formic acid propionic acid aceticacid and butyric acid.
 7. The process of claim 1 wherein the surfacemodifier is a mixture selected from the following:an anionic surfactanta nonionic surfactant a polymeric molecule and an oligomeric molecule.8. The process of claim 1 wherein the clean up and concentration of thedispersion is achieved by one of the methods selected from thefollowing:diafiltration dialysis and evaporation.
 9. The process ofclaim 1 wherein the nanoparticulate dispersion is characterized by aZ-average particle diameter less than 300 nm a measured by photoncorrelation spectroscopy.
 10. The process of claim 1 wherein thepharmaceutical agent is a X-ray contrast agent.
 11. The process of claim1 wherein the nanoparticulate pharmaceutical agent is concentrated tocontain anywhere between 2 to 20% of the agent.
 12. The method of claim1 practiced in any mode selected from the following:a batch process, asemicontinuous batch process and a continuous process.
 13. A process ofpreparing an aqueous dispersion of a pharmaceutical agentcomprising:continuously providing a first solution comprising water andsurface modifier or a mixture thereof, continuously providing a secondsolution comprising a pharmaceutical agent in aqueous base to mix withthe first flow, and immediately neutralizing with an acid solution toprecipitate nanoparticulate dispersion of said pharmaceutical agent asfine particle colloidal dispersions of said pharmaceutical agent,followed by a salt removal step by diafiltration or dialysis and then astep of concentrating the dispersion.
 14. The process of claim 13wherein the pharmaceutical agent is selected from:therapeutic agent anddiagnostic agent.
 15. The process of claim 13 wherein thenanoparticulate dispersion is characterized by a Z-average particlediameter less than 400 nm as measured by photon correlationspectroscopy.
 16. The process of claim 13 wherein the base is selectedfrom any one or a combination of the following:NaOH KOH CsOH trialkylamines and pyridine.
 17. The process of claim 13 wherein theneutralizing acid is selected from:a weak acid and a strong acid. 18.The process of claim 13 wherein the neutralizing acid is selected fromone of the following:HCl HNO₃ HClO₄ H₂ SO₄ formic acid propionic acidacetic acid and butyric acid.
 19. The process of claim 13 wherein thesurface modifier is a mixture selected from the following:an anionicsurfactant a nonionic surfactant a polymeric molecule and an oligomericmolecule.
 20. The process of claim 13 wherein the clean up andconcentration of the dispersion is achieved by one of the methodsselected from the following:diafiltration dialysis and evaporation. 21.The process of claim 13 wherein the nanoparticulate dispersion ischaracterized by a Z-average particle diameter less than 300 nm ameasured by photon correlation spectroscopy.
 22. The process of claim 13wherein the pharmaceutical agent is a X-ray contrast agent.
 23. Theprocess of claim 13 wherein the nanoparticulate pharmaceutical agent isconcentrated to contain anywhere between 2 to 20% of the agent.
 24. Themethod of claim 13 practiced in any mode selected from the following:abatch process, a semicontinuous batch process and a continuous process.25. The process of claim 13 wherein the salt removal step isdiafiltration.
 26. The process of claim 13 wherein the salt removal stepis dialysis.
 27. The process of claim 1 wherein the surface modifier isbase degradable.
 28. A process of preparing an aqueous dispersions of apharmaceutical agent comprising:continuously providing a first flow of asolution comprising water and surface modifier or a mixture thereof,continuously providing a second flow of a second solution comprising apharmaceutical agent in aqueous base, and continuously providing thirdflow of a neutralizing acid solution, and mixing the three flowscontinuously to precipitate a nanoparticulate dispersion of saidpharmaceutical agent to form a fine particle dispersion of the saidpharmaceutical agent, followed by a salt removal step by diafiltrationor dialysis and then a step of concentrating the said dispersion. 29.The process of claim 28 wherein the nanoparticulate dispersion ischaracterized by a Z-average particle diameter less than 400 nm asmeasured by photon correlation spectroscopy.
 30. The process of claim 28wherein the base is selected from any one or a combination of thefollowing:NaOH KOH CsOH trialkyl amines and pyridine.
 31. The process ofclaim 28 wherein the neutralizing acid is selected from:a weak acid anda strong acid.
 32. The process of claim 28 wherein the neutralizing acidis selected from one of the following:HCl HNO₃ HClO₄ H₂ SO₄ formic acidpropionic acid acetic acid and butyric acid.
 33. The process of claim 28wherein the surface modifier is a mixture selected from the following:ananionic surfactant a nonionic surfactant a polymeric molecule and anoligomeric molecule.
 34. The process of claim 28 wherein the clean upand concentration of the dispersion is achieved by one of the methodsselected from the following:diafiltration dialysis and evaporation. 35.The process of claim 28 wherein the nanoparticulate dispersion ischaracterized by a Z-average particle diameter less than 300 nm ameasured by photon correlation spectroscopy.
 36. The process of claim 28wherein the pharmaceutical agent is a X-ray contrast agent.
 37. Theprocess of claim 28 wherein the nanoparticulate pharmaceutical agent isconcentrated to contain anywhere between 2 to 20% of the agent.
 38. Themethod of claim 28 practiced in any mode selected from the following:abatch process, a semicontinuous batch process and a continuous process.39. The method of claim 28 wherein the surface modifier is basedegradable.
 40. The process of claim 28 wherein the continuous mixing iscarried out in:a static mixer or a tubular reactor.
 41. A process ofpreparing an aqueous dispersions of a pharmaceutical agentcomprising:continuously providing a first solution comprising water andsurface modifier or a mixture thereof into a solution comprising apharmaceutical agent in aqueous base to form a first flow, and thenneutralizing the first flow with a second flow of an acid solution at adesired pH to form a fine particle dispersion of a pharmaceutical agent,followed by a step of salt removal by diafiltration or dialysis and thena step of concentrating the said dispersion.
 42. The process of claim 40wherein the nanoparticulate dispersion is characterized by a Z-averageparticle diameter less than 400 nm as measured by photon correlationspectroscopy.
 43. The process of claim 40 wherein the base is selectedfrom any one or a combination of the following:NaOH KOH CsOH trialkylamines and pyridine.
 44. The process of claim 40 wherein theneutralizing acid is selected from:a weak acid and a strong acid. 45.The process of claim 40 wherein the neutralizing acid is selected fromone of the following:HCl HNO₃ HClO₄ H₂ SO₄ formic acid propionic acidacetic acid and butyric acid.
 46. The process of claim 40 wherein thesurface modifier is a mixture selected from the following:an anionicsurfactant a nonionic surfactant a polymeric molecule and an oligomericmolecule.
 47. The process of claim 40 wherein the clean up andconcentration of the dispersion is achieved by one of the methodsselected from the following:diafiltration dialysis and evaporation. 48.The process of claim 40 wherein the nanoparticulate dispersion ischaracterized by a Z-average particle diameter less than 300 nm ameasured by photon correlation spectroscopy.
 49. The process of claim 40wherein the pharmaceutical agent is a X-ray contrast agent.
 50. Theprocess of claim 40 wherein the nanoparticulate pharmaceutical agent isconcentrated to contain anywhere between 2 to 20% of the agent.
 51. Themethod of claim 40 practiced in any mode selected from the following:abatch process, a semicontinuous batch process and a continuous process.52. The surface modifier of the process of claim 40 is base degradable.53. A process of preparing aqueous dispersions of a pharmaceutical agentcomprising:continuously providing a first solution comprising water andsurface modifier or a mixture thereof into a solution comprising apharmaceutical agent in aqueous base to form a first flow, and thenneutralizing the first flow with a second flow of an acid solution at adesired pH to form a fine particle dispersion of a pharmaceutical agent,followed by a step of salt removal by diafiltration or dialysis and thena step of concentrating the said dispersion.
 54. The process of claim 52wherein the neutralization pH is at any pH value between 3.0 and 7.0.55. The process of claim 52 wherein the surface modifier is basedegradable.